Degenerative neurological diseases are responsible for many devastating human illnesses. One of these is multiple sclerosis (MS) which is the foremost crippling disease of young adults; other degenerative disorders include amyotrophic lateral sclerosis and senile dementia of the Alzheimer's type. The causes of these degenerative diseases, and many others are unknown. The studies outlined in this proposal are devoted to research on the etiologies, pathogenesis and treatment of degenerative diseases. Studies on the diagnosis and treatment of MS involve establishment of a MS clinic. The patients in the clinic will then be studied extensively using immunological measurements, electrodiagnostic techniques as well as NMR and CT imaging. The NMR studies appear to be very promising, not only as a new tool in the diagnosis of MS, but also possibly as a means of better understanding the pathogenesis of demyelinating diseases. More basic studies involve identification of the genes that control the incubation periods of two transmissible degenerative disorders, scapie and Creutzfeldt-Jakob disease (CJD). Recent investigations have identified a genetic locus in mice in the D subregion of the major histocompatibility complex (H-2), which controls the length of the CJD incubation period. Alleles coding for longer scrapie and CJD incubation periods were found to be autosomal dominant. Plans to study the demyelination in animals caused by a Japanese isolate of CJD using NMR and CT imaging are also included. Understanding the molecular structure of the slow infectious pathogens causing scrapie and CJD may lead to new insights into the etiologies of other degenerative disorders. A major effort is being devoted to the purification and characterization of the scrapie agent. Improved purification protocols have led to identification of a unique protein that is probably a component of the scrapie agent. The protein was found in purified fractions after radioiodination and electrophorectic analysis on SDS polyacrylamide gels. It has a molecular weight of 27,000 to 30,000 daltons and is resistant to degradation by proteases under nondenaturing conditions. These findings are particularly encouraging since they should permit development of an immunoassay for the agent as well as an affinity purification procedure. The unique molecular properties of the agent distinguish it from other small infectious pathogens, and appear to have defined a new class of microbes.